Mean Intercapillary Distance Research Articles

Visualization of Radial Peripapillary Capillaries Using Optical Coherence Tomography Angiography: The Effect of Image Averaging.

ObjectivesTo assess the effect of image registration and averaging on the visualization and quantification of the radial peripapillary capillary (RPC) network on optical coherence tomography angiography (OCTA).MethodsTwenty-two healthy controls were imaged with a commercial OCTA system (AngioVue, Optovue, Inc.). Ten 10x10° scans of the optic disc were obtained, and the most superficial layer (50-μm slab extending from the inner limiting membrane) was extracted for analysis. Rigid registration was achieved using ImageJ, and averaging of each 2 to 10 frames was performed in five ~2x2° regions of interest (ROI) located 1° from the optic disc margin. The ROI were automatically skeletonized. Signal-to-noise ratio (SNR), number of endpoints and mean capillary length from the skeleton, capillary density, and mean intercapillary distance (ICD) were measured for the reference and each averaged ROI. Repeated measures analysis of variance was used to assess statistical significance. Three patients with primary open angle glaucoma were also imaged to compare RPC density to controls.ResultsQualitatively, vessels appeared smoother and closer to histologic descriptions with increasing number of averaged frames. Quantitatively, number of endpoints decreased by 51%, and SNR, mean capillary length, capillary density, and ICD increased by 44%, 91%, 11%, and 4.5% from single frame to 10-frame averaged, respectively. The 10-frame averaged images from the glaucomatous eyes revealed decreased density correlating to visual field defects and retinal nerve fiber layer thinning.ConclusionsOCTA image registration and averaging is a viable and accessible method to enhance the visualization of RPCs, with significant improvements in image quality and RPC quantitative parameters. With this technique, we will be able to non-invasively and reliably study RPC involvement in diseases such as glaucoma.

Synthetic Capillaries to Control Microscopic Blood Flow.

Capillaries pervade human physiology. The mean intercapillary distance is only about 100 μm in human tissue, which indicates the extent of nutrient diffusion. In engineered tissue the lack of capillaries, along with the associated perfusion, is problematic because it leads to hypoxic stress and necrosis. However, a capillary is not easy to engineer due to its complex cytoarchitecture. Here, it is shown that it is possible to create in vitro, in about 30 min, a tubular microenvironment with an elastic modulus and porosity consistent with human tissue that functionally mimicks a bona fide capillary using “live cell lithography”(LCL) to control the type and position of cells on a composite hydrogel scaffold. Furthermore, it is established that these constructs support the forces associated with blood flow, and produce nutrient gradients similar to those measured in vivo. With LCL, capillaries can be constructed with single cell precision—no other method for tissue engineering offers such precision. Since the time required for assembly scales with the number of cells, this method is likely to be adapted first to create minimal functional units of human tissue that constitute organs, consisting of a heterogeneous population of 100–1000 cells, organized hierarchically to express a predictable function.

Re-evaluating the Use of Voronoi Tessellations in the Assessment of Oxygen Supply from Capillaries in Muscle

The ability to characterise capillary supply plays a key role in developing effective therapeutic interventions for numerous pathological conditions, such as capillary loss in skeletal or cardiac muscle. However, quantifying capillary supply is fraught with difficulties. Averaged measures such as capillary density or mean inter-capillary distance cannot account for the local geometry of the underlying capillary distribution, and thus can only highlight a tissue wide, global hypoxia. Detailed tissue geometry, such as muscle fibre size, has been incorporated into indices of capillary supply by considering the distribution of Voronoi tessellations generated from capillary locations in a plane perpendicular to muscle fibre orientation, implicitly assuming that each Voronoi polygon represents the area of supply of its enclosed capillary. Using a modelling framework to assess the capillary supply capacity under maximal sustainable conditions in muscle, we theoretically demonstrate that Voronoi tessellations often provide an accurate representation of the regions supplied by each capillary. However, we highlight that this use of Voronoi tessellations is inappropriate and inaccurate in the presence of extensive capillary rarefaction and pathological variations in oxygen tension of different capillaries. In such cases, oxygen flux trapping regions are developed to provide a more general representation of the capillary supply regions, in particular incorporating the additional influences of heterogeneity that are absent in the consideration of Voronoi tessellations.

Low-Dose Growth Hormone is Cardioprotective in Uremia

Growth hormone (GH) is required to maintain normal cardiac structure and function and has a positive effect on cardiac remodeling in experimental and possibly human disease. Cardiac resistance to GH develops in the uremic state, perhaps predisposing to the characteristic cardiomyopathy associated with uremia. It was hypothesized that administration of low-dosage GH may have a salutary effect on the cardiac remodeling process in uremia, but because high levels of GH have adverse cardiac effects, administration of high-dosage GH may worsen uremic cardiomyopathy. In rats with chronic renal failure, quantitative cardiac morphology revealed a decrease in total capillary length and capillary length density and an increase in mean intercapillary distance and fibroblast volume density evident. Low-dosage GH prevented these changes. Collagen and TGF-beta immunostaining, increased in chronic renal failure, were also reduced by GH, suggesting a mechanism for its salutary action. Low-dosage GH also prevented thickening of the carotid artery but did not affect aortic pathology. In contrast, high-dosage GH worsened several of these variables. These results suggest that low-dosage GH may benefit the heart and possibly the carotid arteries in chronic renal failure.

Effects of estrogens on cardiovascular structure in uninephrectomized SHRsp rats

The risk of cardiovascular disease in uremic patients is greater in male than in female patients. Estrogens seem to play a cardioprotective role until menopause. Experimental data on the effect of estrogens on cardiovascular damage are controversial and potential underlying mechanisms especially in renal failure have not been fully clarified. Three-month-old female uninephrectomized stroke-prone spontaneously hypertensive (SHRsp) rats were sham-operated or ovariectomized. Subsequently, they received either vehicle (sesame oil) or 17-beta-3 benzoate estradiol (E2) (25 microg/day) or estriol (E3) (0.02 mg/day), respectively. After 3 months the animals were sacrified and the organs were harvested using pressure-controlled perfusion fixation. Stereologic parameters such as capillary length density (L(V)), mean intercapillary distance (MID), and volume density of the interstitial tissue (Vv) were quantitated. Additionally, expression of transforming growth factor-beta (TGF-beta), vascular endothelial growth factor (VEGF), flt-1, endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), endothelin A receptor (ETA) receptor, and alpha estrogen receptor was assessed using immunohistochemistry. Intramyocardial capillaries and the aorta were investigated by morphometric methods. L(V) (mm/mm(3)) was significantly lower (2421 +/- 500) and MID (microm) significantly higher (22.2 +/- 2.33) in vehicle-treated uninephrectomized/ovariectomized compared to uninephrectomized/sham-ovariectomized controls (L(V) 3629 +/- 960, MID 12.7 +/- 2.7) as well as estradiol (L(V) 3340 +/- 739, MID 12.1 +/- 4.96) and estriol (L(V) 4655 +/- 618, MID 14.2 +/- 2.89) treated uninephrectomized/ovariectomized animals. The volume density of the cardiac interstitium was higher in vehicle-treated uninephrectomized/ovariectomized animals compared to uninephrectomized/sham-ovariectomized, estradiol and estriol treated uninephrectomized/ovariectomized rats. The protein level expression of TGF-beta was higher in vehicle treated uninephrectomized/ovariectomized compared to uninephrectomized/sham and all treatment groups. In ovariectomized SHRsp rats with moderate renal failure cardiac lesions were strikingly less after estradiol or estriol treatment. The results document a beneficial role of estrogens on cardiac abnormalities in a model of moderate renal dysfunction.

Microvessel density in muscles of dogs with golden retriever muscular dystrophy

Due to the abundance of muscle, intravascular administration seems required for efficient gene or cell therapy of muscular dystrophy. Here, we examined the skeletal muscle microvasculature to assess if it is altered with dystrophin deficiency. Image analysis of capillaries was performed in three muscles of one- to ten-month-old golden retriever muscular dystrophy (GRMD) dogs and compared with healthy controls. In the gracilis muscle (and in the biceps brachii muscle) of 4- to 10-month-old GRMD dogs, the microvessel density (445±47 microvessels per mm 2), the capillary to fiber ratio (111±26 capillaries per 100 myofibers), and the mean intercapillary distance (49±3 μm), were similar in affected and control dogs. The sartorius cranialis muscle in GRMD dogs showed microvessel depletion and increased intercapillary distance, but unaltered capillary to fiber ratio, relative to the controls. The mean diameter of microvessels and the total vascular area were higher in GRMD muscles than in control ones. In severely affected GRMD muscles at 7–10 months of age, fibrosis was associated with decreased microvessel density, increased intercapillary distance and microvessel diameter, but normal capillary to fiber ratio and total vascular area.

Computerized measurement of intercapillary distance using image analysis in women with cervical intraepithelial neoplasia: correlation with severity

Computerized measurement of intercapillary distance using image analysis in women with cervical intraepithelial neoplasia: correlation with severity

Computerized measurement of intercapillary distance using image analysis in women with cervical intraepithelial neoplasia: correlation with severity

Objective: Widening of the intercapillary distance has been postulated to be associated with increasing severity of the lesion. The purpose of this study was to objectively measure the intercapillary distance in different grades of cervical intraepithelial neoplasia.Methods: We studied 40 patients with a fully visualized squamocolumnar junction and a histopathologic diagnosis of CIN II (n = 24) and CIN III (n = 16). All patients had computer-assisted measurements of the farthest two intercapillary points within each single mosaic as well as the mosaic perimeter (P), and mosaic surface area (SA). The mean intercapillary distance, P, and SA for each patient were calculated by adding all intercapillary distances, Ps, and SAs of the whole mosaic pattern divided by the number of mosaics. A colposcopically directed biopsy was obtained from the same studied area.Results: The mean intercapillary distance in CIN II was 0.064 mm (SD ± 0.023) and in CIN III was 0.117 mm (SD ± 0.062). The difference was statistically significant (P <0.001). In addition, the mean mosaic P in CIN II and CIN III was 0.251 mm (SD ± 0.112) and 0.439 mm (SD ± 0.242), respectively, and the mean mosaic SA was 0.004 mm2 (SD = 0.001) and 0.011 mm2 (SD ± 0.002), respectively. The difference was statistically significant (P <0.05).Conclusions: The results demonstrate increased intercapillary distance, mosaic perimeter, and mosaic surface area with increasing severity of CIN. The increase in intercapillary distance may reflect insufficient vascular adaptation to an accelerated cellular growth rate.

Microvascular perfusion is impaired in a rat model of normotensive sepsis.

We hypothesized that normotensive sepsis affects the ability of the microcirculation to appropriately regulate microregional red blood cell (RBC) flux. An extensor digitorum longus muscle preparation for intravital study was used to compare the distribution of RBC flux and the functional hyperemic response in SHAM rats and rats made septic by cecal ligation and perforation (CLP). Using intravital microscopy, we found that sepsis was associated with a 36% reduction in perfused capillary density (from 35.3 +/- 1.5 to 22.5 +/- 1.0 capillaries/mm of test line) and a 265% increase in stopped-flow capillaries (from 0.9 +/- 0.2 to 3.3 +/- 0.4 capillaries/mm); the spatial distribution of perfused capillaries was also 72% more heterogeneous. Mean intercapillary distance (ICD) increased 30% (from 25.7 +/- 0.8 to 33.5 +/- 1.6 microns), and the proportion of capillary pairs with intercapillary distances > 33.8 microns (the 75th percentile of ICDSHAM) was greater with sepsis. Mean capillary RBC velocity increased 17% in CLP rats (391 vs 333 microns/s). Laser Doppler flowmetry was used to assess the functional hyperemic response of the extensor digitorum longus muscle before and after a period of maximal twitch contraction designed to increase oxygen demand. RBC flux was 36% lower in the CLP rats at rest. After contraction, RBC flux increased in both SHAM and CLP rats; however, the relative increase was less in the CLP group. We concluded that sepsis affects the ability of the skeletal muscle microcirculation to appropriately distribute RBC flux and to respond to increases in oxygen need.

Effects of aging and vincamine derivatives on pericapillary microenvironment: stereological characterization of the cerebral capillary network

Changes in the pericapillary microenvironment of adult (18-month-old) and senescent (27 1 2 -month-old) Fischer-344 rats treated for 6 weeks with daily IP injections of brovincamine or apovincamine (0, 2.5, 5, 10 mg/kg) were correlated with spontaneous locomotor activity and [ 14C]-2-deoxyglucose uptake of the brain. The animals were tested for spontaneous locomotor activity in a tunnel maze. Twenty-four hr after behavioral testing and subsequently after a [ 14C]-2-deoxyglucose injection, brains were removed and capillaries stained with alkaline phosphatase reaction, being later measured with an optical-electronic image analysis technique. Results revealed an increase in intercapillary distance, as a sensitive parameter for capillary density, in the hippocampus (CA1) and in the parietal cortex (area 39) in association with aging. Capillary diameter in the parietal cortex was found to be increased age dependently. A similar age-related increase was also observed in the CA1 field but this age trend was not significant. Chronic treatment with the vincamines produced a dose-dependent reduction in intercapillary distance in senescent animals which approached the level of untreated adult control rats. Significant negative correlations were found between maze locomotion and intercapillary distance among senescent rats. Furthermore, intercapillary distance and local relative 2-deoxyglucose uptake tended to be negatively correlated in both age groups. These findings provide evidence for the working hypothesis that mean intercapillary distance can be considered as an indicator of neuronal activity in the pericapillary microenvironment.

Improved myocardial capillarisation in spontaneously hypertensive rats treated with nifedipine.

The effect of long term administration of nifedipine on myocardial capillarity was studied in spontaneously hypertensive rats. Nifedipine was given for 20 weeks, mixed into commercial rat chow (0.3 g per 1 kg). Untreated spontaneously hypertensive rats had higher arterial blood pressure and developed cardiomegaly when compared with Wistar-Kyoto rats used as controls. Nifedipine administration in spontaneously hypertensive rats lowered the arterial blood pressure and reduced cardiac weight; however, both values remained far above those for controls. Myocardial capillarity was determined using the recently introduced method of capillary domains. Hearts from untreated spontaneously hypertensive rats were characterised by greater and more variable intercapillary spacing than those from controls. The treatment of spontaneously hypertensive rats with nifedipine resulted in normalisation of morphometric indices characterising capillary spacing, probably as a result of stimulation of capillary growth as indicated by a significant decrease in myocyte to capillary ratio. Thus, despite persistent hypertension and cardiomegaly the treatment of spontaneously hypertensive rats with nifedipine restored mean intercapillary distance and index of heterogeneity of capillary spacing to normal values.

Intercapillary distance measurement as an indicator of hypoxia in carcinoma of the cervix uteri

The mean tumor intercapillary distance (ICD) was measured in 44 patients in Stages IIB and III carcinoma of the cervix uteri using a histo-chemical procedure for staining capillary endothelial cells. A mean ICD of 304 ± 30 μm was obtained, which was independent of the clinical stage and histological grade of differentiation. For each tumor, the proportion of ICD's greater than an arbitrarily chosen value of 300 μm (approximately twice the maximum oxygen diffusion range) was calculated using the normal frequency distribution statistics. The mean ICD and this proportion decreased progressively during the course of external beam pelvic irradiation up to a dose of 4000 cGy. The mean ICD was greater in patients who suffered local recurrence within two years than in patients whose tumors remained controlled. This applied to pre-treatment values and measurements performed after the delivery of 2000 and 4000 cGy. The proportion of ICD's greater than 300 μm showed a similar trend. No significant correlation was found between the hemoglobin concentration at time of presentation and either the mean ICD, or the probability of local control. It is proposed that ICD measurement may be a useful tool to identify subgroups of tumors where hypoxia can interfere with the effectiveness of radiotherapy.

The density and distribution of capillaries around a synovial cavity.

The interpretation of trans-synovial fluxes requires a knowledge of the number of capillaries present around the joint cavity, and their depths below the surface of the joint lining. Measurements of capillary numbers, depths and dimensions were therefore carried out by light microscopy on synovial tissue sections from five rabbit knees. In addition the surface area of synovial tissue lining the joint was estimated, and the thickness of the synovium measured. Synovial capillary density was found to be uneven, with respect to both anatomical location in the joint cavity and depth below the synovial surface. The large area of synovium over areolar or adipose tissue was highly vascular (67000-83000 capillaries X cm-2 section; mean intercapillary distance 35-55 micron; 228-329 cm2 endothelium X cm-3 synovium). The small area of synovium over tendons was of very low vascularity (2000 capillaries X cm-2 section). From these data and a previous estimate of net filtration capacity, mean synovial endothelial conductivity was estimated as approximately 16 X 10(-7) cm X s-1 X mmHg-1. The depth distribution of the capillaries was extremely skewed, with a sharp peak at 6-11 micron depth. The rapid decay in capillary density at depths greater than 6-11 micron was partly due to an uneven density of capillaries within the synovium itself; and partly due to a lower density in subsynovial tissues. It was concluded that most synovium has a rich capillary bed which is very superficially located and that the depth of periarticular tissue which is effective in exchange processes with the joint cavity is less than 25 microns.

Lognormal distribution of intercapillary distance in normal and hypertrophic rat heart as estimated by the method of concentric circles: its effect on tissue oxygenation.

The inhomogeneity of the capillary net in the cardiac muscle was estimated using our morphometric measurements in normal and hypertrophic rats hearts. As entry data we used the distribution of tissue at different distances from the nearest capillary as measured by the method of concentric circles and the mean intercapillary distance independently calculated from the capillary density. The derived distribution of intercapillary distances was approximated by lognormal distribution in which the spread can be characterized by a single parameter, namely the log standard deviation. The effect of the log standard deviation on tissue oxygenation was evaluated in normal and hypertrophic hearts, at normoxia and at hypoxia. The mean tissue PO2 and the percentage of anoxic tissue at the venous end of the tissue cylinder were calculated using Krogh's model. Two boundary situations were considered: A) the end-capillary PO2 was assumed to be equal in all capillaries due to compensatory adjustment in blood flow; B) the same flow in all capillaries was assumed resulting in varying end-capillary PO2. The real situation is expected to be between situations A and B. Increased variability of intercapillary distance proved to impair considerably the tissue oxygenation, especially when the results were expressed as a percentage of anoxic tissue. The percentage of anoxic tissue turned out to be a better index of tissue oxygenation than the mean PO2 particularly at hypoxia. The results suggest the presence of at least a partial adjustment of blood flow with respect to the width of tissue cylinder. Without such adjustment, a large part of tissue would become anoxic already in normal hearts at normoxia and this would be further aggravated by hypertrophy and/or hypoxia.

The effect of prolonged propranolol administration on myocardial transmural capillary density in young rabbits.

1. As a sequel to previous evidence that prolonged beta-adrenoceptor blockade in young rabbits led to a relative increase in the capillarity of ventricular muscle, an attempt has been made to localize and quantify the capillary density from epicardium to endocardium in 12-week old rabbits treated for 6 weeks with propranolol (3 mg kg-1) S.C. twice daily and in litter-mates treated with saline (controls). 2. Full-thickness 0.5 micrometers sections of the left ventricular wall were point-counted in 200 micrometers steps. In the controls the capillary 'volume density' decreased progressively below the epicardial surface from a value of 9% to reach a minimum of 7.1% at a depth of 2.5 mm. Capillary density then increased again towards the endocardium, reaching a maximum of 11.5% in the trabeculae carnae (depth 3.5 mm). 3. In the treated animals the capillary density was increased in the mid wall at 2.3 and 2.5 mm, but significantly decreased in the trabeculae at 3.7 mm (P less than 0.05). 4. A more detailed analysis was undertaken at depths of 0.7 (Epi), 2.3 (Endo) and 3.5 mm (Trab), comprising estimates of capillary number, capillary diameter and intercapillary distance, via the stereological parameters of mean intercept length and mean free distance. 5. In the controls the order was Epi greater than Trab greater than Endo for number, Trab greater than Endo greater than Epi for diameter and Endo greater than Epi greater than Trab for intercapillary distance. 6. In the treated rabbits the mean intercapillary distance was significantly reduced in the epicardial (by 17.5%, P less than 0.05) and endocardial zones (by 32%, P less than 0.005), but was not significantly altered (+3.7%, P greater than 0.05) in the trabeculae. 7. The non-uniform distribution of capillaries in the controls illustrates that detection of changes in transmural capillary density requires that the depth of samples be measured from the epicardial surface and not, owing to the presence of trabeculae carnae, from the endocardium. 8. If similar treatment effects were to occur in man, they would suggest that prolonged beta-blockade could induce an increase in capillary density which would render the ventricular mid wall less susceptible to ischaemia.

Arterial blood gases, muscle fiber diameter and intercapillary distance in cardiac hypertrophy of rats with an old myocardial infarction.

In rats with a myocardial infarction due to ligation of the left coronary artery a marked right ventricular hypertrophy developed after 41/2 weeks. At this time no difference against control animals was observed in arterial\(P_{{\text{O}}_2 }\),\(P_{{\text{CO}}_2 }\), pH, ideal alveolar\(P_{{\text{O}}_2 }\), and alveolar-arterial O2 pressure difference, as measured in unanesthetized animals at normoxia. In histological sections of the heart stained by PAS reaction capillaries and muscle fibers were counted, and the mean intercapillary distance and muscle fiber diameter were estimated. In the right ventricle of the rats with myocardial infarction both increased when compared with control animals or with sham-operated rats. Fibercapillary ratio was the same in all three groups. Similar results were obtained in the remaining undamaged tissue of the left ventricle of rats with a myocardial infarction when compared with the left ventricle of control or sham-operated rats. Findings concerning intercapillary distance suggest that also in the myocardium which remains intact during the development of the infarction and later hypertrophies, tissue oxygen transport might be impaired, particularly during a stress situation. Results in the right ventricle of rats with myocardial infarction show an opposite trend against rats exposed chronically to simulated high altitude, where in the hypertrophied right ventricle a shorter intercapillary distance occurs and therefore an improvement of tissue oxygen transport might be expected.

Microcirculation of the epimyocardial layer of the heart. I. A method for in vivo observation of the microcirculation of superficial ventricular myocardium of the heart and capillary flow pattern under normal and hypoxic conditions.

To study microcirculation of the heart in vivo, we developed a new technique of epi-illumination of the beating rat ventricular myocardium. Five tiny needles connected to the operation table were horizontally inserted into the ventricular myocardium just beneath the epicardium in order to restrict cardiac movement during contraction and to enhance the amount of light reflected from the structures under study. The in vivo light and fluorescent microscopy were performed with the Ultropak and the Fluopak systems (Leitz) combined with a highly sensitive television camera and recording system. In 142 individual in vivo measurements (6 animals) the mean capillary diameter amounted to 6.0 +/- 1.0 mu. In the same experiments, the mean intercapillary distance was 18.7 +/- 1.7 mu. In agreement with the literature, the capillaries of the epimyocardial layer of the rat heart demonstrate a mixed countercurrent flow pattern. In contrast to other authors, we observed no recruitment of resting capillaries after hypoxia.

Intercapillary distances and capillary reserve in right and left ventricles: Significance for control of tissue pO 2

Distances between capillaries perfused with erythrocytes were measured by stopmotion microcinematography in rat hearts beating in situ. In 18 animals mean intercapillary distance (ICD) was 14.44 μm in the left ventricle and 15.47 μm in the right. These values correspond to about 2815 and 2530 perfused capillaries/mm 2. respectively. The difference in ICD is statistically significant. Calculations indicate that the shorter diffusion path in the working left ventricle has a significant effect on O 2 transport. On the other hand, minimum ICD is longer and maximum capillary density is smaller in the left ventricle. Thus a larger fraction of the available capillaries is utilized in the normal, working left ventricle. The estimated capillary reserve is 750/mm 2 in the left ventricle and 1500/mm 2 in the right. The shorter ICD in the beating left ventricle appears to reflect control of coronary precapillary sphincters by local tissue pO 2.

A new instrument for the measurement of tissue pO2 of human fetal scalp

Measurement of fetal scalp tissue pO2 may be a way of monitoring fetal oxygenation continuously. A membrane-covered flush-type oxygen electrode was developed for this purpose. This electrode measured qualitative changes in tissue pO2. Movement artifacts were reduced by the membrane coating and by the matching of electrode diameter to mean intercapillary distance, the electrode then monitoring mean tissue pO2. Maternal inhalation of 50 per cent oxygen increased scalp tissue pO2. Following normal birth the scalp tissue pO2 increased. Neonatal inspiration of 100 per cent oxygen produced a marked increase in scalp tissue pO2. In one baby born in a poor clinical condition, recovery was mirrored by changes in scalp tissue pO2. In 2 patients with slowing of the fetal heart rate during contractions, scalp tissue pO2 decerased simultaneously. Because the electrode cannot be considered accurately quantitative the information obtained has only been useful in elucidating fetal oxygenation in relation to particular events. At present it has no use in clinical obstetrics.